Host Genetic Factors Associated with CNS Disease of HIV-Infected Children

与艾滋病毒感染儿童中枢神经系统疾病相关的宿主遗传因素

• 批准号: 8448656
• 负责人: STEPHEN A SPECTOR
• 金额: $ 70.21万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8448656
• 关键词: AIDS/HIV problem; Adolescent; Adult; Affect; African; Age; Alleles; Anti-Retroviral Agents; Central Nervous System Diseases; Child; Code; Cognitive; Cohort Studies; Complication; Copy Number Polymorphism; Developed Countries; Developing Countries; Development; Developmental Delay Disorders; Disease; Drug usage; Encephalopathies; Ethnic group; Exons; Genes; Genetic; Genetic Models; Genetic Polymorphism; Genotype; HIV; HIV Infections; Hispanics; Illicit Drugs; Impaired cognition; Impairment; Incidence; Infection; Longitudinal Studies; Matched Group; Modeling; Natural Immunity; Neurocognitive; Neuropathogenesis; Not Hispanic or Latino; Outcome; Pathogenesis; Pathway interactions; Perinatal; Proteins; Protocols documentation; Research; Risk; Risk Factors; Single Nucleotide Polymorphism; South Africa; Subgroup; Technology; Testing; Time; Variant; adaptive immunity; antiretroviral therapy; base; cognitive function; cohort; exome sequencing; gene function; genetic variant; indexing; insight; neuropsychiatry; novel; novel strategies; patient population; prevent; receptor; socioeconomics; solution hybridization; tool; virus host interaction

DESCRIPTION (provided by applicant): Severe developmental delays, cognitive impairment and encephalopathy (which for consistency are referred to as HIV-associated Neurocognitive Disorders [HAND]) occurred in 30-50% of perinatally infected children prior to the availability of effective combination antiretroviral therapy (ART). While with ART the incidence of encephalopathy has been reduced, severe cognitive impairment is still identified in 15-20% of HIV-infected children. Additionally, although much research has been performed on HAND, the neuropathogenesis of CNS impairment remains to be elucidated. The research proposed will apply state-of-the-art exome sequencing technology to identify the host genetic factors associated with HAND in children. The specific aims of this proposal are: Aim 1: Apply whole exome sequencing (WES) to identify novel candidate genetic variants associated with HAND in a discovery cohort of perinatally infected children. In this aim, WES will be used to identify novel genetic locus variants and pathways that are associated with HAND in children. The hypothesis to be tested is that by examining all protein-coding sequences (exomes) in addition to HLA and killer Ig-like receptor (KIR) alleles in 500 HIV-infected children equally divided between subjects with HAND and those with normal neurocognitive and neurodevelopmental function gene locus variants will be identified which are associated with CNS disease. Aim 2: Evaluate the associations of the genetic variants with CNS disease in replication cohorts of HIV-infected children in the U.S. Having identified novel genetic variants that are associated with HAND in Aim 1, the association of ~500 variants and specific HLA/KIR genotypes of highest significance in the discovery cohort will be tested for association in two U.S. replication cohorts with similar ethnic and socioeconomic backgrounds as the discovery cohort. Targeted exome sequencing and genotyping of specific HLA and KIR SNPs will be performed. Aim 3: Examine the genetic variants identified in Aims 1 and 2 associated with CNS disease of children in the U.S. for association of these polymorphisms with CNS disease in a cohort of HIV-infected children in South Africa. The hypothesis to be tested is that although a cohort of children born in South Africa differs significantly from those born in the U.S., genes carrying variants identified to alter the risk of HIV-related CNS disease in U.S. born children will also be important determinants of risk for children from South Africa. For these studies, targeted exome sequencing and specific HLA and KIR genotypes will be applied to South African HIV-infected children who have undergone extensive neuropsychometric and developmental testing. To our knowledge, our research has access to the largest cohorts of well-characterized HIV-infected children with CNS outcomes in the world, and will for the first time apply exome sequencing to large number of HIV-infected children. The findings of this research will provide insights into the pathogenesis of HAND and suggest novel strategies how to treat and to prevent the CNS disease associated with HIV.

描述（申请人提供）：严重发育迟缓，认知障碍和脑病（对于一致性而言，这被称为HIV相关的神经认知障碍[手]）发生在30-50％的围产期感染儿童中，在有效组合抗病毒治疗（ART）之前。虽然ART降低了脑病的发生率，但在15-20％的HIV感染儿童中仍发现严重的认知障碍。此外，尽管手头上已经进行了大量研究，但中枢神经系统损伤的神经病发生仍有待阐明。提出的研究将应用最先进的外显子组测序技术来识别与儿童手相关的宿主遗传因素。该提案的具体目的是：目标1：应用整个外显子组测序（WES）来识别与手相关的新型候选遗传变异，并在发现围产期感染的儿童中与手相关。在此目标中，WES将用于识别与儿童手相关的新型遗传基因座变体和途径。要测试的假设是，除了检查500名HIV感染儿童中的HLA和杀手Ig样受体（KIR）等位基因外，通过手动与正常神经认知和神经发育功能基因级别的正常神经认知和正常的神经认知和神经性基因差异的患者相关的所有蛋白质编码序列（EXOMES（EXOMES）都与HARD的500名等位基因相关。目标2：评估遗传变异与CNS疾病的关联在美国的复制群体中的复制群体中，在AIM 1中确定了与Hand in AIM 1相关的新型遗传变异，〜500种变异的关联和特定的HLA/KIR在两种基因上的基因与发现同类群体中的相似之处的相似之处将在两种相似之处中进行，这将在两种情况下与发现同类的相似之处相似。发现队列。将进行特定HLA和KIR SNP的靶向外显子组测序和基因分型。 AIM 3：检查与美国儿童中枢神经系统疾病相关的AIM 1和2中确定的遗传变异，以在南非的一组HIV感染的儿童中与CNS疾病相关。要检验的假设是，尽管南非出生的一群儿童与在美国出生的儿童有很大不同，但携带变种的基因却鉴定出来改变了美国出生的儿童中与HIV相关的中枢神经系统疾病的风险，这也是对来自南非儿童的风险的重要决定因素。在这些研究中，有针对性的外显子组测序以及特定的HLA和KIR基因型将应用于接受广泛神经心理测试和发育测试的南非感染的儿童。据我们所知，我们的研究可以进入世界上有CNS结果的最多良好的艾滋病毒感染儿童，并将首次对大量的HIV感染儿童进行外显子组测序。这项研究的结果将为手的发病机理提供见解，并提出了如何治疗和预防与HIV相关的中枢神经系统疾病的新型策略。